In recent years, methods of diagnosing or treating various diseases using antibodies have been studied. Particularly, because of the target specificity of antibodies, various therapeutic methods using antibodies have been developed, and various types of drugs containing antibodies, for example, antibody-drug conjugates (ADCs), have been developed. Thus, studies have been continuously conducted to increase the in vivo stability of antibodies or antibody-drug conjugates and maximize the therapeutic effects thereof.
Among them, antibody-drug conjugates generally have the disadvantage of low in vivo stability compared to natural antibodies, but have been developed in order to overcome the disadvantages (low therapeutic effects) of natural antibodies by conjugating them to drugs. Various antibody-drug conjugates in which drugs having certain medical effects, such as cytotoxin, are conjugated to target-specific antibodies, have been developed. In particular, a method of inducing cancer cell death by cytotoxin conjugated to a cancer cell-specific antibody is a method that is actually currently used.
However, such antibody-drug conjugates generally have low in vivo stability compared to natural antibodies. Furthermore, if drug antibody ratio (DAR) is increased in order to increase therapeutic effects, there will be various technical problems to be solved. First, an increase in drug antibody ratio should not interfere with the antigen-binding ability and Fc function of antibodies for target-specific therapy, should lead to an increase in therapeutic effects, and should not reduce the in vivo stability (i.e., blood half-life) of antibody-drug conjugates. The object of the current antibody-drug conjugate preparation field is to maintain the highest possible antibody drug ratio in view of the above-described technical problems. In particular, considering that the expression level of cancer cell surface antigens is low, the highest possible drug antibody ratio (DAR) should be maintained in order to maintain high cytotoxicity. However, if DAR reaches 8, there is a problem in that the blood half-life of the antibody-drug conjugate decreases due to the effect of the hydrophobic drug conjugated to the antibody so that the toxicity thereof can increase and in vivo efficacy thereof can decrease.
Under this background, the present inventors have made extensive efforts to develop a technology capable of preparing an antibody-drug conjugate which maintains the antigen-binding activity of a parent antibody, exhibits excellent anticancer effects, and has low drug toxicity and excellent in vivo efficacy. As a result, the present inventors have found that, when a drug is conjugated to the N-terminus of the heavy chain or light chain of an antibody, the antibody-drug conjugate has excellent blood stability and anticancer activity while having low in vivo toxicity compared to previously reported antibody-drug conjugates, thereby completing the present invention.